JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
September 2022
I-M26

Signalment (JPC #2152K): Dog

 

HISTORY: This dog had multifocal alopecia, crusting, and hyperpigmentation of the skin of the head and trunk.

 

HISTOPATHOLOGIC DESCRIPTION:  Haired skin: There are multifocal to confluent subcorneal pustules that span several hair follicles, measuring up to 1 x 5.5 mm and are filled with numerous viable neutrophils, few eosinophils, and moderate numbers of individualized acantholytic keratinocytes with a central nucleus, rounded margins, and deeply eosinophilic cytoplasm, occasionally these acantholytic cells are adhered to the eroded stratum corneum (cling on cell). Diffusely within the underlying epidermis, the stratum spinosum is thickened (acanthosis); these keratinocytes exhibit prominent intercellular bridging (spongiosis) and cytoplasmic vacuolation (intracellular edema) and there is a moderate neutrophilic exocytosis. The less-affected adjacent epidermis is characterized by mild acanthosis, spongiosis, and orthokeratotic hyperkeratosis.  Diffusely at the dermal-epidermal junction there is a lichenoid band of inflammation composed of moderate numbers of neutrophils and lymphocytes with fewer plasma cells, eosinophils, and macrophages. These inflammatory cells occasionally infiltrate the deeper dermis and surround adnexa. Rare neutrophils are also within follicular epithelium. Dermal collagen bundles are separated by clear space and there are dilated lymphatics (edema). Apocrine glands are mildly ectatic.

 

MORPHOLOGIC DIAGNOSIS: Haired skin: Subcorneal pustules, multifocal, moderate, with marked acantholysis and moderate neutrophilic dermatitis, breed unspecified, canine.

 

ETIOLOGIC DIAGNOSIS: Autoimmune dermatitis

 

CONDITION:  Pemphigus foliaceus

 

GENERAL DISCUSSION:

• Pemphigus: A group of autoimmune skin diseases characterized grossly by the formation of pustules, vesicles, bullae, erosions, ulcers and histologically by acantholysis (loss of adhesion between epithelial cells)
• Pemphigus foliaceus (PF), although uncommon, is the most common form of pemphigus in domestic animals, followed by discoid and systemic lupus erythematosus
• PF typically occurs in middle-aged dogs, with no sex predilection
• Genetic predisposition in Akita, bearded collie, chow chow, dachshund, Doberman pinscher, Finnish spitz, Newfoundland, Chinese shar-pei, English springer spaniel and schipperke
• There are three forms:
  • Spontaneous: Akitas and chow chows
  • Drug induced: Labrador retrievers and Doberman pinschers
  • Disease associated: Dogs with chronic allergic or pruritic skin disease

 

PATHOGENESIS: 

• Circulating pemphigus autoantibodies target cell-adhesion molecules which assists in binding keratinocytes together at the desmosome
• Pemphigus foliaceus lesions occur only on haired skin, where the antibody targets a desmosomal glycoprotein that resides in the upper layers of the epidermis (type II hypersensitivity reaction)
  • The major autoantigen in dogs is desmocollin-1 (DSC1), a transmembrane calcium-dependent desmosomal glycoprotein involved in intracellular adhesions
  • Only a minority of dogs with PF will have against another desmosomal cadherin, desmoglein-1 (DSG1), which is the autoantigen in humans
  • Autoantibodies have not been studied in PF in horses, goats, or cats, the other species in which PF has been reported
• Often arises spontaneously, but can be triggered by adverse drug reactions as well as topical flea and tick preventatives
• Autoantibody binding to DSC1> antibody-induced cleavage of extracellular domain DSC1 > loss of cohesion between keratinocytes (acantholysis) > formation of superficial epidermal vesicles > formation of pustules and crusts
• It is also thought that autoantibody binding to adhesion molecules may stimulate the secretion of urokinase-type plasminogen activator (uPa) > activates plasminogen> loss of cohesion between keratinocytes

 

TYPICAL CLINICAL FINDINGS: 

• Pruritis is evident in approximately 25% of cases
• Systemic signs are often seen in cases with generalized disease, including anorexia, depression, fever, weight loss

 

TYPICAL GROSS FINDINGS: 

• Vesicles that rapidly transition into pustules with crusting, often bilaterally symmetrical on the face (especially nasal planum), ears, footpads, clawbeds, and/or groin; may be generalized in >50% of cases
• Pustules are transient, easily rupture, and lead to thick crusts with variable scaling, alopecia, and erosions
• Nasal depigmentation leads to photosensitization

 

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

• Superficial intraepidermal (subcorneal and intragranular) pustular dermatitis that typically involves the corneal layer and granular cell layer
  • Ruptured pustules can form a thick inflammatory crust that contains acantholytic cells
  • Pustules often span several follicles and contain myriad neutrophils and often eosinophils
  • Acantholytic cells: pustules contain numerous acantholytic keratinocytes that are free, partially adherent or adhered to the overlying stratum corneum; these “cling-ons” are only seen in PF; the crust is useful to assess as it likely contains acantholytic cells
• External root sheath of hair follicle can have acantholytic keratinocytes
• Lichenoid (band-like) or superficial perivascular to interstitial dermal inflammation possible
• Footpad lesions include villous hyperkeratosis, swelling, and fissures

 

ADDITIONAL DIAGNOSTIC TESTS:

• Immunofluorescence or Immunohistochemistry (IHC) may demonstrate immunoglobulin (IgG) in the intercellular space in all layers of the suprabasilar epidermis or in the superficial epidermis; this is not specific for PF, and there are frequent false positive and false negative results
• Cytology: Direct imprint of underside of crust or aspiration of pustuleà nondegenerate neutrophils and acantholytic cells (individualized keratinocytes) and usually no bacteria

 

DIFFERENTIAL DIAGNOSIS: 

For gross findings (pustular and crusting dermatitis):

• Superficial bacterial folliculitis is the top differential diagnosis for PF: exfoliative toxins may cleave desmoglein 1 resulting in acantholytic cells
  • In PF the pustules span multiple hair follicles whereas in bacterial folliculitis are usually centered on single follicles
  • Acantholytic cells are more numerous in PF than in superficial folliculitis
  • “Cling-on” stratum granulosum cells are only present in PF
• Bullous impetigo: Usually ventral abdominal in pubescent dogs
  • Impetigo does not involve hair follicles
• Superficial spreading pyoderma: Smaller pustules and Dunstan's blue line of basophilic debris in superficial keratin layers
• Superficial pustular dermatophytosis: Usually young animals, is often asymmetrical on face
• Demodicosis
• Seborrhea
• Discoid and systemic lupus erythematosus
• Zinc responsive dermatosis
• Sebaceous adenitis
• Mycosis fungoides: Less symmetry

 

For microscopic findings (subcorneal pustules):

• Bullous impetigo: Cocci; less severe acantholysis
• Acantholytic dermatophytosis - GMS, PAS reveals hyphae
• Pemphigus erythematosus: Milder form usually limited to facial lesions (not footpads); deposits of IgG/IgM along the basement membrane and intercellular spaces; basal cell damage (interface dermatitis) is prominent  

 

COMPARATIVE PATHOLOGY: 

• Cat – thick crusts are often bilaterally symmetrical on the face and ears (pinnal margin)
• Horse – PF is the most common autoimmune skin disease in equids; begins on the face or distal extremities, or may be localized to coronets; no age or sex predilections; Appaloosas may be predisposed; over 50% have concurrent systemic clinical signs
• Goat – face, abdomen, limbs, perineal region, tail
• Barbary sheep
• Arabian oryx – Similar lesions as described in other domestic animals (bilaterally symmetrical lesions hyperkeratotic skin lesions affecting the pinnae, face, nasal planum, distal legs, and tail tip (Curtiss, Vet Pathol 2021)

 

References: 

1. Curtiss JB, Lewis M, Mitchell EP. Pemphigus foliaceus in Arabian oryx (Oryx leucoryx). Vet Pathol. 2021;58(6):1-5.
2. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Infectious nodular and diffuse granulomatous and pyogranulomatous diseases of the dermis. In: Skin Diseases of the Dog and Cat, Clinical and Histopathological Diagnosis. 2nd ed. Ames, IA: Blackwell; 2005: 13018, 265-266, 415-417.  
3. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Saunders Elsevier; 2016: 601-602.
4. Raskin RE, Conrado FO. Integumentary system. In: Raskin RE, Meyer DJ, eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023: 42-43.
5. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1192-1194.

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